How air pollution may trigger lung cancer in never-smokers: towards molecular cancer prevention?

A new mechanism has been identified through which very small pollutant particles in the air may trigger lung cancer in people who have never smoked, paving the way for new preventive strategies and the development of novel therapies. The effect at hand is driven by an influx of macrophages and an increase in the inflammatory mediator interleukin-1β, which promotes carcinogenesis in airway cells.

Until now, reasons why lung cancer develops in never-smokers has been largely elusive, especially with respect to the influence of underlying environmental circumstances. For over two decades, the air pollutant, particulate matter (PM), is known to be associated with the risk of non-small cell lung cancer (NSCLC). However, a direct causative link and a mechanism of action for this oncogenic potential was missing. Therefore, a study from the Francis Crick Institute in London investigated whether air pollutants, derived from fossil fuel, combustion, etc. are directly causing lung cancer in never-smokers.

Study design

The study involved 447,932 individuals to address the associations of increasing 2.5 µm PM (PM2.5) concentrations with cancer risk. Researchers performed ultra-deep profiling of 247 normal lung tissue samples, analysed normal lung tissue from humans and mice following exposures to PM, and investigated the consequences of PM on tumour promotion in mouse lung cancer models.

Results

First of all, researchers determined associations between cancer risk and varying concentrations of PM2.5. In fact, higher PM2.5 concentrations were associated with an increased risk for mesothelioma, lung, anal, small intestine, GBM, lip, oral cavity and pharynx and laryngeal carcinomas in UK Biobank. In addition, increasing PM2.5 levels also proved to be associated with an increased risk for EGFR-mutated NSCLC in England, South-Korea and Taiwan.

To investigate this further, mice models mimicking healthy never-smokers were exposed to either PM2.5 or filtered air for two hours.  By these experiments, researchers found that air pollution drives the influx of macrophages, which release the inflammatory mediator interleukin-1β, driving the expansion of cells with the EGFR mutations in response to exposure to PM2.5. Furthermore, a blockade of interleukin-1β inhibited lung cancer initiation. These findings were consistent with data from a previous large clinical trial showing a dose dependent reduction in lung cancer incidence when people were treated with the anti-IL-1β antibody, canakinumab.

In a final series of experiments, the Crick Institute researchers used state-of-the-art, ultradeep mutational profiling of 247 small samples of normal lung tissue and found EGFR and KRAS driver mutations in 15% and 53% of normal lung samples, respectively. According to the research team, driver mutations in EGFR and KRAS genes are a likely consequence of ageing and only weakly potentiate cancer in laboratory models. However, when lung cells with these mutations were exposed to air pollutants, more cancers were reported and these occurred more quickly than when lung cells with these mutations were not exposed to pollutants, suggesting that air pollution promotes the initiation of lung cancer in cells harbouring driver gene mutations. The laboratory findings now raise the question of whether these data could pave the way to new molecular-based prevention approaches and development of targeted therapies for non-smokers who are at-risk of lung cancer i.e., those harbouring EGFR mutations.

Conclusion

These results shed light on the aetiology of EGFR-mutated lung cancer, particularly in never-smokers, and suggest that oncogenic mutations may be necessary but insufficient for tumour formation. These data reveal a mechanistic basis for PM driven lung cancer in the absence of classical carcinogen-driven mutagenesis, reminiscent of models of tumour initiation and promotion proposed 70 years ago, providing evidence to limit air pollution and opportunities for molecular targeted cancer prevention.

Reference

Swanton C, et al. Mechanism of action and an actionable inflammatory axis for air pollution induced non-small cell lung cancer: towards molecular cancer prevention. Presented at ESMO 2022; Abstract LBA1.